Non-alcoholic fatty liver disease (NAFLD) is an increasing health problem when left untreated. NAFLD is defined as accumulation of fat in 5% of the hepatocytes. NAFLD can convert into non-alcoholic steatohepatitis (NASH) which is defined as inflammatory NAFLD. Both NAFLD and NASH are observed in individuals suffering from metabolic syndrome and type 2 diabetes (T2D). Agents which increase the insulin sensitivity for T2D treatment are thiazolidinediones (TZDs) which target nuclear peroxisome proliferator-activated receptor γ (PPARγ). Therefore, TZD has been investigated as a potential agent for the treatment of NAFLD and NASH. Other members of nuclear receptor families such as constitutive androstane receptor (CAR), farnesoid X receptor (FXR), pregnane and xenobiotic receptor (PXR) and liver X receptor regulate metabolic responses across multiple organ system during eating and fasting. These nuclear receptors are regulators of the axis of gut, liver, and adipose tissue. Abnormal NRs signaling is associated with NAFLD, especially in obesity, increased intestinal permeability of lipopolysaccharide (LPS) followed by inflammation, abnormal hepatic lipid metabolism, and insulin insensitivity. We review nuclear receptor superfamily, its architectural structure, signaling and possible signaling interference in the development of NAFLD. Due to the lack of treatment for NAFLD or NASH, patients' only option is changes in their lifestyle which include weight reduction and less fat intake. This review also examined the possibility of NR mediated treatment of NAFLD. Current clinical trials are focused on separate treatments of different NAFLD states, such as steatosis, inflammation, insulin insensitivity, obesity, and dyslipidemia. Nuclear receptor mediated transcription does not occur in isolation rather many works in coordination, i.e., one NR activation affects other NRs, a process referred to as NR crosstalk resulting in transrepression/transactivation. For the treatment of NAFLD, a tissue specific ligand devoid of NR-crosstalk is likely needed.